Check out Geoff’s narration
The GIST
The Blog
A blog on Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) might not be what you expect on a chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID website. While CCHFV is a major problem in Africa, the Middle East, and Asia it’s not in North America or Europe. A recent study suggests, though, that it may not matter where a bug comes from when it comes to postviral illnesses.
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The Crimean-Congo Hemorrhagic Fever (CCHF) Virus may sound exotic but its postviral effects looked all too familiar.
Thanks to Kajsa for digging this one up – I never would have seen it otherwise. The only word in the title “Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection” that gives any clue to the goodies contained inside is the word “temporal”: the researchers followed the CCHFV patients over time and that made all the difference.
The Study
In this Swedish/UK/Turkish study, the Swedish (Karolinska Institute) and UK researchers appear to have done the deep dive into the biology while the Turkish researchers provided the sick patients. Good for the Swedish Research Council for funding an interesting study.
With a fatality ranging from 5% (Turkey) to up to 50% in some African countries, CCHVF is a nasty disease that makes the coronavirus – at least in some countries – look like a relative piker. All the patients in this study were hospitalized and all experienced fever plus there was headache (97%), muscle ache (93%), weakness (90%), and nausea and/or vomiting (70%). Some sort of bleeding problem was observed in half of the patients.
This study assessed the transcriptomics (gene expression) of immune cells in 30 hospitalized patients and 30 healthy controls from infection onset to about a month later. Some high-level data analyses including network-based systems, analysis, digital cell quantification (DCQ), and temporal pathogenic alterations by time series clustering) were used.
THE GIST
- Check out Geoff’s narration of the GIST and the Blog on the top of the blog.
- A blog on Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) might not be what you expect on a chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID website. A recent study, though, suggests that it might not matter where a pathogen comes from when it comes to postviral illnesses.
- CCHFV – a major threat in Africa, the Middle East, and Asia – can produce high fatality rates in some parts of Africa. This Swedish/Turkish study assessed the gene expression of immune cells to determine how the immune cells of hospitalized CCHFV patients responded to the infection over time.
- Energy demands soared in the early stages of the infection creating a “hypermetabolic state” in the immune cells as they revved up their engines to battle the pathogen. The upregulation of ATP production, increased use of amino acids, and a turn toward fatty acid oxidation during the infection demonstrated the cells were under tremendous energy and cellular stressors.
- The ability to generate energy was crucial: patients whose cells had to turn to alternative energy sources to fight the virus were sicker off.
- That early hypermetabolic period had its cost. Thirty days later, after the pathogen had apparently been vanquished (or mostly vanquished) several findings suggested an “energy maladjustment” had occurred and the patient’s immune cells were in a state of “metabolic insufficiency”.
- Despite having apparently fought off the virus, the vast majority of patients (83%) were experiencing fatigue and pain and many also experienced weight loss, headache, heart palpitations, and sweating; i.e. they were in a state of postviral illness similar to that seen in ME/CFS and long COVID.
- The authors concluded that “metabolic rewiring” i.e. problems with cellular energy production “potentially leads to postviral fatigue” and noted how many different viral infections (Dengue fever, SARS-CoV-2, the West Nile, Ebola, and Marburg viruses) produce symptoms (fatigue/weakness, headache, dizziness, musculoskeletal pain, and cognitive and sleep disorders) similar to those found in ME/CFS.
- The key finding is that when it comes to postviral illnesses it may all be about the ability (or inability) of our cells to produce energy. Something appeared to happen early in the infection to affect energy production 30 days later. While we don’t know if this problem persists the findings from this Crimean-Congo virus study are very similar to what we see in conditions like long COVID and ME/CFS.
- Evidence of natural killer, T, and B-cell exhaustion has been found in ME/CFS and a recent Stanford presentation found that overstressed mitochondria in ME/CFS patients T-cells were breaking down causing them to release high levels of free radicals/reactive oxygen species. Metabolomic studies in another post-viral illness – post-treatment Lyme Disease Syndrome have also stressed problems with energy production.
- The big question is what happens during the infection to whack the energy-producing elements of the cell leaving it in an exhausted state.
Findings
The results were fascinating. The usual suspects – mostly innate immune cells (myeloid cells, monocytes, NK cells, neutrophils, dendritic cells and T-cells) – showed up in spades during the infection, but the real juice was in the metabolic findings.
The immune cells ramped up their energy production during the acute phase of the infection.
Energy demands soared in the early stages of the infection creating a “hypermetabolic state” in the immune cells as they revved up their engines to battle the pathogen. The upregulation of ATP production, increased use of amino acids, and a turn toward fatty acid oxidation during the infection demonstrated the cells were under tremendous energy and cellular stressors.
Those patients whose immune cells couldn’t keep up with the metabolic demands were forced to turn to alternative anaerobic energy pathways (glycolysis/pyruvate metabolism) to generate energy. These patients were worse off – suggesting that an inability of their cells to generate suitable amounts of energy resulted in a more severe illness.
That early hypermetabolic period had its cost. Thirty days later, after the pathogen had apparently been vanquished (or mostly vanquished) several findings suggested their immune cells had not recovered. Their energy production (glycolysis, TCA cycle, OXPHOS) fell so much that the researchers concluded that an “energy maladjustment” had occurred and they were in a state of “metabolic insufficiency”
The patients looked like it. The vast majority of patients (83%) were experiencing fatigue strong enough to inhibit their daily activities leading the authors to conclude they were in a postviral fatigue state. Besides fatigue, musculoskeletal pain (75%), anorexia (50%), weight loss (50%), headache (38%), palpitation (38%), and sweating (38%) were found.
The authors concluded that “metabolic rewiring during the recovery phase potentially leads to postviral fatigue”. Bringing chronic fatigue syndrome (ME/CFS) into the mix they noted the different viral infections (Dengue fever, SARS-CoV-2, the West Nile, Ebola, and Marburg viruses) all produce neuropsychiatric symptoms (fatigue/weakness, headache, dizziness, musculoskeletal pain, and cognitive and sleep disorders) similar to those found in ME/CFS. (They could have mentioned more pathogens: herpesviruses, Giardia, Coxsackie B).
Because the study lasted for 30 days we don’t know if the metabolic changes were maintained or if they were associated with the development of “long CCHF”.
The metabolic rewiring seen in these shorter-duration patients appears to mirror, though, those seen in people with ME/CFS and long COVID; i.e. downregulation of aerobic energy production and increased use of a dirty fuel source – amino acids.
Recapitulation
Energy production plummeted in the “recovery” period leaving the patients fatigued, in pain, etc.
So here we have an interesting scenario. In the acute or early phase of the infection, the immune cells experience a dramatic increase in the demand for their energy – a demand that metabolically rewires the cell causing increased ATP production via the OXPHOS pathway in the mitochondria, and begins burning more fatty acids and amino acids.
The more effective the immune cells at meeting their energy demands the better they can fight off the infection and the better off the patients are. In some people, their cellular energy reserves get tapped out, and they resort to using an alternative energy source (pyruvate/glycolysis). People in this group tend to be sicker.
During the recovery phase, the energy-producing pathways were downregulated – but not to normal levels – downregulated to the point of “metabolic insufficiency”. At this point, about 30 days after the original infection, many patients reported they’re fatigued, are in pain, can’t sleep well, have cognitive problems, etc.; i.e. they appear to have postviral fatigue.
The key finding is that it’s all about energy! How well a person can fend off a pathogen depends on the ability of their immune cells to produce high amounts of energy. If the immune cells can’t do that well they will get sicker.
The big question, of course, is why the immune cells found themselves in a hypometabolic state 30 days later or even years later in ME/CFS.
The Postviral Energy Drain
A similar energy drain may be occurring in the NK, T, and B-cells in ME/CFS. Vishnu Shankar’s ME/CFS study (unpublished) suggested that overstressed mitochondria in T-cells were breaking down and releasing high levels of free radicals/reactive oxygen species. Those high levels then damaged the mitochondria – causing even more oxidative stress – and throwing people with ME/CFS into a vicious cycle. Mark Davis even suggested that the energy drain from the immune cells could be siphoning energy off from the brain resulting in brain fog.
Something similar may be going on in the B-cells. A 2018 study found these cells had been metabolically rewired as well. The more glycolysis was used to produce energy and the greater the lactate production (a by-product of glycolysis), the more likely the B-cells in ME/CFS patients remained in a “naïve” or less active functional state. A 2024 study suggested that the B-cells in ME/CFS were dragging. Once stimulated the ME/CFS patient’s B-cells exhibited lower mitochondrial masses than the healthy control cells plus they, too, turned to using essential amino acids for energy.
Over in another post-pathogenic condition – post-treatment Lyme disease syndrome (PTLDS) – a metabolomic study highlighted alterations in an array of factors (glycerophospholipid metabolism, bile acid, carnitine) that are broadly involved in fatty acid metabolism and energy production. The authors noted the dramatic overlap between PTLDS and ME/CFS:
The classes of metabolites identified in this study are similar to those described in patients with chronic fatigue syndrome (CFS). Similar to our findings, changes in glycerophospholipid, aromatic and branched-chain amino acid, carnitine, bile acid, fatty acid, and sphingolipid metabolism were described in studies involving patients with ME/CFS.
Something appears to happen early in an infection to whack the ability (or desire?) of these immune cells to produce energy. They may be hunkering down to avoid damage aka Naviaux’s Dauer proposition and/or may be too damaged to function properly. In any case, it’s startling to see energy problems crop up in so many immune cells.
Given we know of ME/CFS and long COVID, though, something like that makes sense. In an upcoming “What’s Up Doc?” blog, Nancy Klimas will note that the immune system has so many backup systems that it would require multiple hits for the viral reactivation found in ME/CFS and long COVID to occur.
The authors of the CCHRF paper ended by stating “A better understanding of the immuno-metabolic mechanism of the postviral fatigue in CCHF patients can identify therapeutic targets for better and faster recovery.” One wonders if the sentence would better read “A better understanding of the immuno-metabolic mechanism of post-viral fatigue can identify therapeutic targets for better and faster recovery”
Thanks Cort 🙂 Great article. Somebody’s got to figure it out with so many lines of evidence pointing in the same direction, broken mitochondria and a wacked out immune system.
Why would “they” want to find a cure…way more money to be made off long term treatment.
I think we can all agree by now that dam near everything revolves around money.
I keep thinking to myself, those poor people like me that begin their undiagnosed journey, which for me never did find an ending….I found it on my own after being on some websites….only then,30 years in ,when I took the information I found online, to an ND,did I get recognition.that alone tells me the system is badly broken. My current ND still won’t try anything unless I come forward with some info I’ve found.i just kept thinking to myself….
GEEEZ…”this must be some kind of game they keep playing with me” of coarse, we are all very vulnerable folks with brain fog and all the other symptoms.ive always felt like less of a person with all of this illness
Mi ricorda larticolo su l”itaconate shunt” in ME/CFS e long covid
Thanks for another thought provoking article, Cort. Not to be too picky but Lyme disease is not a virus, it’s a bacteria.
There is evidence that “post” treatment Lyme disease is a matter of inadequate treatment and that the pathogen is still active.
Recent high dose dapsone treatment seems to put some people into remission. (See Horowitz & Freeman re High Dose Dapsone.)
🙂 yes – definitely a bacteria.
We’re certainly getting evidence in long COVID that the pathogen in whatever form is still there and may be provoking an immune reaction. I think that’s a nice scenario as it means we have to get better at getting at those pathogens either through drugs or by enhancing the immune system.
Post treatment Lyme disease is not a postviral illness – it’s a post-pathogenic? post-infection? illness. Can’t forget the bacteria. The Dubbo studies included a bacterial infection. It’s amazing that these very different pathogens seem to be producing similar results.
Dapsone – interesting! Used to treat acne and leprosy…You just never know what might work. Thanks@
This is the therapy that is helping those with persistent(?) Lyme, which some folks call post treatment Lyme disease (PTLD):
“Comparison of the Efficacy of Longer versus Shorter Pulsed High Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome with Bartonellosis and Associated Coinfections
by Richard I. Horowitz 1,2,*, John Fallon 2 and Phyllis R. Freeman 2
Microorganisms 2023, 11(9), 2301; https://doi.org/10.3390/microorganisms11092301
Published: 12 September 2023
If dapsone isn’t treating an infection, then what is it doing?
If the infection isn’t persistent, why do we find it on autopsy in those who have “had” PTLD?
We have also found SARS-CoV-2 on autopsy years(!) after the first infection.
So are we really sure the infections are gone, or are they still lurking?
Regarding the commonality of symptoms regardless of the initial pathogen, perhaps low grade persistence takes you to the same finite number of biochemical pathways?
Anyhow. thanks for facilitating the discussion, Cort.
If we are tossing everything in the same bucket, should we add protozoa? Is there a post-protozoa condition similar to post viral illness or post-Lyme? Perhaps there is something to be learned by looking at those little guys?
Absolutely! How did we miss the protozoa? Giardia alone…..We even have evidence for it – a subset of FM patients still ill ten years later I think it was – same symptoms (!)
I dearly hope we can find a core problem….it would be so much simpler. We have different biologies in GWI and ME/CFS but Dr. Klimas’s modeling work suggests the same treatment will help with both…may it be so.
Infection hiding behind inflammation,therfore the antibiotics can’t get to the said location due to inflammation 🤷♂️
PAISs: https://en.wikipedia.org/wiki/Post-acute_infection_syndrome 🙂
Hi Cort, thanks for the interesting article. However, I don’t think “It’s amazing that these very different pathogens seem to be producing similar results.” after all. The human immune system is the common factor here.
The hyper-metabolic state sounds like an “all in” desperate response for survival vs the usual immune responses . What triggers this “hyper-metabolic” state? Is it a “necessary” response or is it the pathogen “draining” the immune system and leaving it in a state like an over-stretched elastic band or spring, which can no longer return to its original state? Is our immune response being conned into taking desperate actions?
I have ME/CFS myself, since 2016, and the cognitive effects make it difficult for me to order my thoughts. I hope I have contributed to the discussion. Thanks.
This makes sense. It is the normal process for immune cells to ramp up metabolic needs during response to any acute infection, they have to massively proliferate and undergo mutations to become more specific to target the pathogens (B cells) which all requires lots of energy. That is also why we feel tired during any normal infection, our body is trying to force us to rest to conserve energy to go toward fighting the pathogen. As noted here the big question is why the switch to the hypometabolic state, because normal immune responses should clear the viral infection but as we know that doesn’t happen with many viruses, and the immune system has built-in mechanisms to try to not allow ongoing constant ramped up responses, so maybe it is a backfiring trying to downregulate the continued response but doesn’t really work right? I still would like to know more if the fatigue here is related to ongoing inflammation or neuroinflammation and messed up nervous system function like we see in ME/CFS and fibro, because I am not sure how having hypometabolic immune cells would directly cause fatigue. If the metabolism of all other cells is messed up then yes, but not just immune cells (that would really only lead to immunodeficiency would be my guess).
Might be this process induced autoimmunity?
Emily,
Indeed, is the mitochondrial problem pan-body or just restricted to the innate immune cells? Myhill, Booth and McLaren-Howard looked at the ATP production of lymphocytes (later peripheral-blood white cells) in PwME/CFS and found a strong correlation between fatigue and the inability to produce ATP of these immune cells. They also found that for most PwME/CFS, there was an inability to transfer metabolites across the mitochondrial membrane, which happens at special translocator sites. Why would the membranes of the mitochondria of innate immune cells be the only ones in the body to suffer this fate? Why hasn’t there been follow-up research into blocked mitochondrial membranes, which could be at the heart of our disease?
I listened to Akiko Iwasaki yesterday, one of her updates in an AMA update on long covid, and she mentioned stress and other triggers too for reactivation etc. She divided longcovid (and ME/CFS) in four categories. She noted that several categories probably was applicable in the same person.
https://youtu.be/fEjwilGWApg?feature=shared .
And after that I read a text from Karolinska Institute on MS, and I have been thinking that EBV was the most suspect for triggering MS, but this is a text that gives an even broader set of culprits. I know it is in Swedish, but I think Google translate will do the trick. It was forst published in 2016.
https://ki.se/forskning/multipel-skleros-en-nytolkad-sjukdom?fbclid=IwZXh0bgNhZW0CMTEAAR0j_ZGmnMx8FoMfQViUMYZWko7sTCQFF8q96vi8oRiyIweNJ7gPJssG_cU_aem_ASb14E6raqBmUFA2RCyuzPH1BACbo1R1DoNAmJlTZWDaFHx9–P4V6_wD_NqWJFl8XQ_gCum5MWrFtWtI6PegknI
Why am I posting these? As Akiki said in her webinar even stress/other impacts could cause or be a part of the cause, and MS research are so clear that there are many cooperating factors involved. MS is quite similar to ME in many ways.
This stuff that happens to the mitocondria, the fight/flight/play dead and Dauer or hightened/lowered immune system due to stress (could help the reactivation?).
It’s almost like a theraphy session, haft sentences on my behalf. As you say Cort, every bit of the puzzle matters and having yet another article like this Swedish/UK/Turkish study confirming and adding to one part of the puzzle is important.
Thanks, again, Kajsa – looking forward to watching Akiko’s talk 🙂
With long covid I’m pretty sure my fatigue was related to the gut because it improved over time on PHGG and certain bifido strains. But I’ve got covid again and there is another problem not solved by prebiotics, the nasal immunity problem. This may be due to the fatigued t cells, or it might be some kind of microbiome or tissue specific issue, but I get every single virus and it takes forever to get it out of my nose. After covid that has also meant problems with recurring loss of smell , ear infections, hearing loss and eustachian dysfunction. I’m tempted to try rinsing my sinuses with phgg! Someone needs to develop a prebiotic rinse safe for sinuses that reduces inflammation and supports healthy strains, similar to phgg tbe gut.
I would not suggest that! Your gut and nose have different microbiomes! The good news is “they”are working on it. https://www.sciencealert.com/your-nose-bacteria-might-play-a-role-in-good-health-just-like-the-gut-microbiome. In the meantime using supplements to lower overall cytokines might help as well as using essential oils. https://www.healthline.com/health/essential-oils-for-sinus-congestion#research. I’d also suggest looking at the website below. Yes it says Treat Lyme but it is for all kinds of diseases and issues. Following Dr Ross suggestions and Cort’s I’ve improved dramatically in the last 9 years! https://www.treatlyme.net/
Yes, this is exactly what happened to me….infected in 1981…then years of weird vague symptoms but UNABLE to catch a flu,virus etc. For a few years….then…KERBOOM!!…And a big KERBOOM!! that seemed to last a very long time of fighting inside…like a war inside….fight,fight,fight, rest…fight ,fight, fight, rest…fight ,fight, fight ,rest
Until finally the fight couldn’t fight anymore…now im in a state of all beat up with lots of remaining damage arthritis, tissue damage, connective tissue not connected….and easily catch the first bug that’s going around.
I try to live away from people for the simple reason of not wanting to catch another bug, for obvious reasons.
I think that maybe if we can detox all the dead debris that’s been left behind from the war, we’d all feel better
Fasting
Interesting that Dr. Robert Naviaux’s Cell Death (Dauer) Theory suggests the body is Hypometabolic…in a hibernation-like state. This could explain why we seem to have so many subsets of disease symptoms in ME/CFS. Naviaux thought the century-old drug, Suramin (which was and is used to treat African Sleeping Sickness) would be a treatment option….not only for ME/CFS but for Autism Spectrum Disorder as well. Too bad he wasn’t able to get enough of the drug to do necessary testing.
Ouch – I didn’t that attempt had failed. Darn! Naviau’s ideas really do seem to permeate this field. I hear them popping up again and again….
They are still working on Suramin for autism. Not Naviaux, but a company called Paxmedica (Naviaux is on their advisory board). Unfortunately they seem to have dropped the intention to test in long covid from their website.
Looks like they plan to submit their New Drug Application for Suramin for African Sleeping Sickness this year. If they then get a Priority Review Voucher they can monetize it to aid further phases of study for Suramin in autism.
Not the best of news for long covid/ME, but at least the drug is still in play. If it is approved for autism, one hopes they would then look to use it in other illnesses too. ME/CFS is number two (after autism) on the list of illnesses Naviaux wanted to trial Suramin for on his website.
Very interesting (read the gist).
What I wonder is, did all these 30 patients still have symptoms at day 30? And, if so, is this a virus that gives all patients postviral symptoms?
I think it would be really interesting to do this kind of temporal analysis including both on patients who quickly recover after a viral infection and those who retain postviral symptoms – might help hone it on what makes the difference.
Now add this to the mix, as of May 1, 2024
https://www.nature.com/articles/d41586-024-01259-2
“Found: the dial in the brain that controls the immune system”
….the vagus nerve and the brain stem….
From the journal Nature.